Women comprise an increasing proportion of all HIV-infected persons, and most of these women are of child-bearing age. As more HIV-infected women become pregnant, the impact of pregnancy on the mother's HIV disease progression becomes increasingly important. Studies conducted early in the HIV epidemic reported a possible association between pregnancy and accelerated HIV disease progression, particularly in developing countries. In a recent study conducted among women receiving care at our medical center in the era of highly active antiretroviral therapy (HAART), pregnancy was associated with a significantly lower risk of HIV disease progression. These results suggest a possible beneficial interaction between pregnancy and HAART in HIV-infected women. Consistent with these findings is a study showing that HIV-1 RNA is well controlled during pregnancy, but it then rebounds postpartum despite stable antiretroviral therapy. A decrease in generalized immune cell activation is thought to be critical to maintain pregnancy, and regulatory T cells (T regs) have recently emerged as important players in such materno-fetal tolerance. Recent studies in humans have demonstrated an increase in the number of circulating T reg cells during pregnancy in HIV-uninfected women, and diminished numbers of T regs have been associated with immunologic rejection of the fetus. T regs have also been proposed as a key population that regulates the immune response in HIV-1 infection. T regs limit activation of CD4+ T cells and thus decrease the availability of target cells for HIV infection and limit CD8+ effector function that in turn could limit HIV-associated immune dysregulation. Little is known about whether pregnancy-induced T regs have an effect on HIV-1 infection. The Aims of this Research Career Award are to characterize pregnancy-related changes in T regs frequency and immune activation in HIV-1-infected women on HAART, and to determine whether these changes are associated with changes in viral load by: 1. assessing frequency of T regs and immune activation markers in HIV-1-infected pregnant women without post-partum viral rebound; 2. comparinging frequency of T regs and immune activation markers during the third trimester in HIV-1- infected pregnant women with and without post-partum viral rebound; 3. performing a prospective study to assess frequency of T regs and immune activation markers in HIV-1-infected and HIV-1-uninfected pregnant women. RELEVANCE: The overall Objective of this proposal is to critically evaluate whether the decrease in immune activation will be observed during pregnancy in HIV-1-infected women receiving HAART, and if so, whether it is associated with a reduced risk of HIV disease progression post-partum. Mechanistic understanding of the possible interplay between pregnancy, HAART, and HIV infection may allow better understanding of HIV disease progression in all HIV-infected persons.